Department of Physiology and Neurobiology, Basic Medical College, Ningxia Medical University, Yinchuan 750004, China.
Sci China Life Sci. 2012 Apr;55(4):358-66. doi: 10.1007/s11427-012-4311-1. Epub 2012 May 9.
Salusins are regulatory peptides that affect cardiovascular function. We previously reported that salusin-α and -β protected cultured cardiomyocytes from serum deprivation-induced cell death through upregulating glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) resident protein whose overexpression acts as a marker and suppressor of ER stress. The present study examined whether salusin-α and -β inhibit ER stress in ischemic myocardium. In a rat model of myocardial infarction created by ligating the left anterior descending coronary artery (LAD), salusin-α or -β was intravenously injected at 5 or 15 nmol kg(-1) 15 min prior to 2 h of LAD occlusion. The high dose of salusin-α and -β significantly improved heart function and hemodynamics in LAD-occluded rats, but had no effects in sham-operated rats. The arrhythmias caused by LAD occlusion were markedly attenuated by salusin-α and -β. The apoptotic rate in ischemic myocardium was reduced from 31.5%±3.7% to 19.8%±2.2% and 12.3%±2.2%, and the infarct size was reduced from 53.4%±4.0% of the risk area to 26.5%±9.7% and 23.7%±8.9% by 15 nmol kg(-1) salusin-α and -β, respectively. Furthermore, salusin-α and -β prevented the activation of GRP78 and ER stress-specific apoptotic effectors caspase-12 and CHOP (C/EBP homologous protein), and attenuated the reduction of an ER stress-associated antiapoptotic protein Bcl-2 in ischemic cardiac tissue. The salusins also inhibited the ER stress induced by tunicamycin in cultured rat H9c2 cardiomyocytes. These results indicate that salusins protect myocardium against ischemic injury by inhibiting ER stress and ER stress-associated apoptosis.
沙利素是调节心血管功能的肽类。我们之前的研究表明，沙利素-α和-β 通过上调葡萄糖调节蛋白 78（GRP78）来保护培养的心肌细胞免受血清剥夺诱导的细胞死亡，GRP78 是内质网（ER）驻留蛋白，其过表达作为 ER 应激的标志物和抑制剂。本研究探讨了沙利素-α和-β 是否抑制缺血心肌中的 ER 应激。在结扎左前降支冠状动脉（LAD）创建的大鼠心肌梗死模型中，在 LAD 闭塞前 15 分钟静脉注射 5 或 15 nmol kg（-1）的沙利素-α或-β。高剂量的沙利素-α和-β 显著改善了 LAD 闭塞大鼠的心脏功能和血液动力学，但在假手术大鼠中没有作用。沙利素-α和-β 显著减轻了由 LAD 闭塞引起的心律失常。缺血心肌中的细胞凋亡率从 31.5%±3.7%降至 19.8%±2.2%和 12.3%±2.2%，梗塞面积从缺血区域的 53.4%±4.0%降至 15 nmol kg（-1）沙利素-α和-β 分别为 26.5%±9.7%和 23.7%±8.9%。此外，沙利素-α和-β 阻止了 GRP78 的激活和 ER 应激特异性凋亡效应子半胱氨酸天冬氨酸蛋白酶-12 和 CHOP（C/EBP 同源蛋白），并减轻了缺血心脏组织中与 ER 应激相关的抗凋亡蛋白 Bcl-2 的减少。沙利素还抑制了培养的大鼠 H9c2 心肌细胞中衣霉素诱导的 ER 应激。这些结果表明，沙利素通过抑制 ER 应激和 ER 应激相关的凋亡来保护心肌免受缺血性损伤。
